Multiparticulates are well known dosage forms that comprise a multiplicity of particles whose totality represents the intended therapeutically useful dose of a drug. When taken orally, multiparticulates generally disperse freely in the gastrointestinal (GI) tract, maximize absorption, and minimize side effects. See, for example, Multiparticulate Oral Drug Delivery (Marcel Dekker, 1994), and Pharmaceutical Pelletization Technology (Marcel Dekker, 1989).
A specific example is disclosed in Curatolo et al., U.S. Pat. No. 6,068,859, which discloses multiparticulates that provide controlled release of azithromycin.
Yet another example of a multiparticulate is disclosed in Burnside, U.S. 2001/0006650 A1, published Jul. 5, 2001, which discloses a solid solution beadlet. The beadlet comprises (i) a hydrophobic long chain fatty acid or ester component; (ii) a surfactant; and (iii) a therapeutic agent. The therapeutic agent such as a drug is described as being dissolved in the hydrophobic component to form a single phase solid solution.
Multiparticulates are often used to provide controlled-release of a drug. One problem when formulating a multiparticulate that controls the release of the drug is setting the release rate of the drug. The release rate of the drug depends on a variety of factors, including the carrier used to form the multiparticulate and the amount of drug in the multiparticulate. Often it is desired to provide a particular release rate. However, it may be difficult to achieve a particular release rate using a particular carrier composition.
Other formulation problems result from the melt-congeal process often used to form multiparticulates. The multiparticulates are preferably formed into round beads or spheres. However, some carriers, when melted and then solidified, do not form round beads. Instead, the carriers may solidify into rods, strings, or other non-spherical shapes, often referred to as “floss.” The result is very irregularly shaped multiparticulates that are difficult to process into dosage forms.
It is also desired to maintain the chemical and physical stability of the drug in the multiparticulate. This is often best achieved by maintaining the crystallinity of the drug in the multiparticulate. Thus, it is desired to use carriers and processing conditions that avoid solubilization of the drug and so maintain the drug's crystallinity.
But the presence of substantial amounts of crystalline drug in the molten carrier during the melt-congeal process presents its own problem. The molten carrier containing the crystalline drug must be atomized to form multiparticulates. The presence of large amounts of crystalline drug in the molten mixture can lead to a high viscosity of the mixture, which in turn can make it difficult to process the molten mixture to form the multiparticulates.
Another constraint on the selection of carriers is that the drug may react with the materials used to form the multiparticulates. Since the melt-congeal process occurs at elevated temperatures, the materials should be inert at elevated temperatures as well. Thus, it is desired to use carriers that are relatively inert to reduce degradation of the drug or other excipients.
What is therefore desired is a multiparticulate composition which allows controlled release of the drug over a wide range of release rates, which allows the release rate to be set at a predetermined rate, which may be formed using a melt-congeal process, and which maintains the crystallinity of the drug during the melt-congeal process and in the resulting multiparticulate.